The branch is focusing on identifying the role of neutrophil extracellular traps in the development of autoimmune responses and end-organ damage in systemic diseases including lupus (SLE), rheumatoid arthritis (RA) and systemic vasculitides (AAV). During this year, our group demonstrated in various animal models the role that NETs may play in vivo with regards to atherogenesis, renal damage, type I Interferon production and skin manifestations in mouse models of lupus and atherosclerosis. We have identified peptidylarginine deiminase-IV as a potential therapeutic target in these diseases, given its role in NET formation. Furthermore, we characterized NETs as an important in vivo source of the oxidative enzyme machinery that contributes to modifications of lipoprotein promoting atherogenesis. Lupus patients have evidence of aberrant HDL, which is highly oxidized and displays abnormal function, as measured by reverse cholesterol transport. We identified enzymes externalized in NETs as a highly competent machinery leading to HDL oxidation. Abrogation of NET formation in vivo significantly reduces HDL oxidation. Following a bench to bedside approach we are in the process of establishing a well-characterized cardiovascular lupus cohort which is being followed prospectively for identification of novel biomarkers that predict progression of vascular inflammation, endothelial dysfunction and premature vascular events. We are using sophisticated imaging and functional vascular assays to quantify these abnormalities in lupus patients. We have also reported that NETs are a source of citrullinated autoantigens and this phenomenon may be important in the initiation and perpetuation of aberrant inflammatory responses in rheumatoid arthritis. We found that NET formation is enhanced in RA both in blood and synovium, NETs externalize citrullinated proteins that are known to be important autoantigens in RA. Autoantibodies to citrullinate proteins in turn enhance NET formation. NETs promote synovial fibroblast inflammation. Ongoing work is attempting to further elucidate the interplay between NETs and synovial fibroblasts as an amplification mechanism in inflammatory arthritides.